GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.

GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored. Here we examined the effects of GATA-2 gene dosage on the generation and expansion of HSCs in several hematopoietic sites throughout mouse development. We show that a haploid dose of GATA-2 severely reduces production and expansion of HSCs specifically in the aorta-gonad-mesonephros region (which autonomously generates the first HSCs), whereas quantitative reduction of HSCs is minimal or unchanged in yolk sac, fetal liver, and adult bone marrow. However, HSCs in all these ontogenically distinct anatomical sites are qualitatively defective in serial or competitive transplantation assays. Also, cytotoxic drug-induced regeneration studies show a clear GATA-2 dose-related proliferation defect in adult bone marrow. Thus, GATA-2 plays at least two functionally distinct roles during ontogeny of HSCs: the production and expansion of HSCs in the aorta-gonad-mesonephros and the proliferation of HSCs in the adult bone marrow.

Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis.

Tumors develop through successive stages characterized by changes in gene expression and protein function. Gene expression profiling of pancreatic islet tumors in a mouse model of cancer revealed upregulation of cathepsin cysteine proteases. Cathepsin activity was assessed using chemical probes allowing biochemical and in vivo imaging, revealing increased activity associated with the angiogenic vasculature and invasive fronts of carcinomas, and differential expression in immune, endothelial, and cancer cells. A broad-spectrum cysteine cathepsin inhibitor was used to pharmacologically knock out cathepsin function at different stages of tumorigenesis, impairing angiogenic switching in progenitor lesions, as well as tumor growth, vascularity, and invasiveness. Cysteine cathepsins are also upregulated during HPV16-induced cervical carcinogenesis, further encouraging consideration of this protease family as a therapeutic target in human cancers.